Shock resistant to conventional treatment with fluid and vasopressor was common in nonsurvivors in the recent outbreak of B. anthracis infections in the US. In prior studies, although blood pressure was reduced similarly with lethal lipopolysaccharide (LPS) and Bacillus anthracis lethal toxin (LeTx) challenges, plasma cytokine and nitric oxide levels, while increased with LPS were not with LeTx. The purpose of the present study was to determine whether fluid support would have different effects comparing these two challenges. Sprague-Dawley rats with indwelling central venous and systemic arterial catheters received 24 h infusions of LPS or LeTx. At the initiation of challenge, animals were randomized to also receive 24 h infusions with increasing doses of normal saline (NS) (2.5, 5, 10, 20 or 40 ml/kg/h) or no NS (control). Similar regimens of fluid had been shown previously to increase survival rates with E. coli challenge in this rat model. Animals were observed for 168 h. With LPS, compared to survival rates with no fluid (1 survivor of 8 animals studied, 13%) increasing fluid doses either increased survival or did not worsen it (3 of 7, 38%; 4 of 8, 50%; 2 of 8, 25%; 1 of 6, 17%; and 1 of 7, 14%). With LeTx however, compared to survival rates with no fluid (7 of 15, 47%) increasing fluid doses all worsened survival (5 of 16, 31%; 3 of 16, 19%; 1 of 15, 7%; 3 of 15, 20%; and 3 of 15, 20%). Across all doses, these fluid regimens increased survival rates with LPS but worsened it with LeTx in patterns that were significantly different (p=0.05 comparing the effects of fluid with these two challenges). Not only does the production of inflammatory mediators differ comparing LPS and LeTx challenge in this rat model, but the response to fluid support does also. Extrapolated clinically, these findings suggest that better defining the efficacy of fluid resuscitation for shock related to LeTx during B. anthracis infection may be necessary. At present studies are underway determining whether altering the timing of fluid will increase their efficacy with LeTx challenge. Studies are planned in which the effects of catecholamine administration will be compared with LeTx and LPS challenges.